The invention relates to the production of recombinant proteins and their use in biomedical therapies.
Hypertension is the most common cardiovascular disease. Many people in the United States suffer from what is commonly referred to as xe2x80x9chigh blood pressure.xe2x80x9d That is, have a systolic and/or diastolic blood pressure above 140/90.
Elevated arterial pressure causes pathological changes in the vasculatury and hypertrophy of the left ventricle. As a consequence, hypertension has many deleterious effects on the body. For example, it is the principal cause of stroke, leads to disease of the coronary arteries with myocardial infarction and sudden cardiac death, and is a major contributor to cardiac failure, renal insufficiency, and dissecting aneurism of the aorta.
Pharmacological treatment of patients with high blood pressure will reduce morbidity, disability, and mortality from cardiovascular disease. Effective antihypertensive therapy will almost completely prevent hemorrhagic strokes, cardiac failure, and renal insufficiency due to hypertension. Overall, there is a marked reduction in total strokes.
Antihypertensive drugs can be classified according to their sites or mechanisms of action. Arterial pressure is the product of cardiac output and peripheral vascular resistance. Thus, such pressure can be lowered by actions of drugs on either the peripheral resistance or the cardiac output, or both. Drugs may reduce the cardiac output by either inhibiting myocardial contractility or decreasing ventricular filling pressure. Reduction in ventricular filling pressure may be achieved by actions on the venous tone or on blood volume via renal effects. Drugs can reduce peripheral resistance by acting on smooth muscle to cause relaxation of resistance vessels or by interfering with the activity of systems that produce constriction of resistance vessels.
Vasodilators are a class of drugs which are commonly employed in the therapy of heart failure, high blood pressure, and other various conditions characterized by constricted blood vessels. Such conditions include Raynaud""s syndrome, certain post-surgical complications of brain surgery involving subarachnoid hemorrhage, heart failure, angina pectoris, and hypertension.
Proteins from biting insects, particularly blood-feeding arthropods, have been shown to contain numerous pharmacologically-active substances, including vasodilating substances. The saliva from such insects contain such substances to counteract many of the host""s hemostatic defenses. Among these secretions are the potent vasodilating substances that heighten blood flow to the feeding site.
The salivary components responsible for vasodilation are extremely varied as revealed by the recent characterization of purified factors from several genera. Of several species of ticks analyzed, the saliva of each contained a lipid-derived prostaglandin that could account for vasodilative activity. Further, vasodilators play a role in skin-associated immune response.
Specific immunity has evolved as a sophisticated defense mechanism of higher organisms. In humans, cell-mediated immunity and humoral immunity are the two major mechanisms. Both of these responses have a high level of specificity directed to antigenic epitopes expressed on molecular components of foreign agents.
There are several clinical settings where it is desirable to suppress an immune response. These situations include organ transplantation, treatment of autoimmune disorders, and prevention of Rh hemolytic disease of the newborn.
Because of the importance of providing hypertension therapies, potent vasodilators are needed. Additionally, agents which are capable of modulating the immune response and aiding in wound healing are additionally desirable.
Purified vasoactive proteins from the salivary glands of the blood-feeding black fly, Simulium sp. are provided. The proteins find use in biomedical therapies, particularly where peripheral resistance and stenoses are problems. The proteins are also useful as regulators of the immune response and as promoters of wound healing.
The nucleotide sequence encoding the proteins, as well as methods for producing recombinant protein, are additionally provided.